When it was first used in the 1990s to treat an immune deficiency, gene therapy — treating diseases by correcting a patient's faulty genes — was touted as a breakthrough that was likely to cure scores of hereditary diseases. But when 18-year-old Jessie Gelsinger died in 1999 after having a corrected gene injected to treat his liver disease, the field became wary, and researchers found it difficult to fix the problems associated with the technique.

Now, more than 20 years later, long-term survival data are giving researchers hope that gene therapy might still fulfil its potential. Two studies published today in Science Translational Medicine show that 13 of 16 children treated with gene therapy for severe combined immune deficiency, or SCID, have had their immune systems restored, and one other is in remission for leukaemia that developed due to the gene therapy treatment. Children born with SCID lack a functioning immune system, making them extremely vulnerable to infections, which are usually serious and sometimes even life-threatening.

The best treatment for the disease is a bone marrow transplant from an immunologically matched sibling. But when no matched donor is available, unmatched donors, such as parents, are recruited; these transplants are only around 70 percent successful. Gaspar says that the succcess of gene therapy now rivals or betters that seen in these unmatched donor situations.

"Our papers add to the evidence that gene therapy can be corrective of these conditions, and that it gives long-lasting, robust reconstitution of the immune system," says author Bobby Gaspar, a physician at the Institute of Child Health at University College London. The results, along with those from previously reported SCID trials, suggest that gene therapy is slowly proving its worth.

Researchers are now testing the technique in other immune disorders, as well as in other conditions often treated with transplantion, such as β-thalassaemia and X-linked adrenoleukodystrophy. Gene therapy has also been used to treat leukemia and a rare eye disorder.

"We are way ahead of where we were five years ago," says Donald Kohn of Children's Hospital Los Angeles, who wrote a commentary accompanying the studies published today.

Cancer scares
In 2001, the leader of the first successful SCID gene-therapy trial4, Alain Fischer at the Necker Hospital for Sick Children in Paris, reported that a child in the trial had developed leukaemia (see 'Gene therapy: A tragic setback'). The leukaemia is thought to have been induced by a component in the modified virus, or vector, the researchers used to insert the correct gene into the boy's cells.

In total, five of the 20 children in Paris and London who have received gene therapy for a form of the disease that is linked to the X-chromosome have developed leukaemia, and one has died.

Of the 30 children worldwide who have been treated with gene therapy for another form of SCID, marked by a deficiency in the enzyme adenosine deaminase (ADA), none has developed leukemia, and 21 have been able to discontinue the enzyme replacement therapy usually needed to keep the disease at bay.

But Gaspar says that gene therapy is still a better alternative than the conventional treatment for X-linked SCID in some children because 19 of the 20 children who have received gene therapy for X-linked SCID are still alive. When told these odds, all parents of children with X-linked SCID have opted for gene therapy, Gaspar says.

Gaspar's team is now working with other researchers around the world to test vectors that lack the cancer-causing component in children with X-linked SCID and another immune deficiency, called Wiskott-Aldrich Syndrome. They also hope to test the new vectors in ADA-SCID.

How to move this new batch of trials forward safely and effectively will be one of the major topics of discussion at a Gene Therapy Symposium being convened next month in Bethesda, Maryland, by the US National Institutes of Health and the American Society of Gene and Cell Therapy in Milwaukee, Wisconsin.

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